Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.


Issue 10, 2014
Previous Article Next Article

Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states

Author affiliations

Abstract

Peramivir is a potent inhibitor of influenza neuraminidase, and is used clinically to treat influenza infections. The substantial potency of peramivir for its target suggests that similar structures might be useful as lead compounds for designing inhibitors of related viral, mammalian, or bacterial neuraminidases. At the same time, the large number of rotatable bonds in peramivir's structure led us to consider the conformational flexibility for the drug, since a more flexible scaffold might be a disadvantage in cases where isoenzyme selectivity is required. An examination of previously published X-ray data for the free and bound states of the drug, together with solution-phase NMR, conformational analysis, and DFT calculations leads us to conclude that peramivir undergoes a substantial conformational shift upon binding to the neuraminidase active site. Peramivir's previously unrecognized conformational flexibility may be a liability for peramivir itself, or for future applications of the underlying cyclopentane scaffold. Our analysis finds a consensus among enzyme-bound conformations of the inhibitor, and suggests that favoring this conformation could be used to develop inhibitors with greater potency or isoform selectivity.

Graphical abstract: Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states

Back to tab navigation

Supplementary files

Article information


Submitted
15 Apr 2014
Accepted
17 Jun 2014
First published
19 Jun 2014

This article is Open Access

Med. Chem. Commun., 2014,5, 1483-1488
Article type
Concise Article
Author version available

Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states

M. R. Richards, M. G. Brant, M. J. Boulanger, C. W. Cairo and J. E. Wulff, Med. Chem. Commun., 2014, 5, 1483
DOI: 10.1039/C4MD00168K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

Reproduced material should be attributed as follows:

  • For reproduction of material from NJC:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
  • For reproduction of material from PCCP:
    [Original citation] - Published by the PCCP Owner Societies.
  • For reproduction of material from PPS:
    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
  • For reproduction of material from all other RSC journals:
    [Original citation] - Published by The Royal Society of Chemistry.

Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.


Search articles by author

Spotlight

Advertisements